This invention relates to a composition comprising sucralfate and a coated antacid with controlled onset of reaction (hereinafter referred to as a coated antacid). The composition of the present invention is useful per se as a pharmaceutical composition, especially a gastrointestinal drug, and also as a pharmaceutical base composition for production of other medicines by its blending with appropriate active ingredients.
When the composition of the present invention is taken orally as a drug, sucralfate, a constituent of the composition, reacts with gastric acid in the stomach to form an adhesive substance (paste), which adheres to the mucosa, exhibiting an antiulcer effect and an ulcer inhibiting/healing effect. Then, the coated antacid held in the paste shows a persistent antacid action. That is, the present invention relates to a DDS-type composition as a gastrointestinal drug comprising sucralfate and an antacid, which permits the pharmacological effect of sucralfate to appear fully, and the antacid to dwell in the stomach, thereby revealing its antacid effect for a long time. The invention is also concerned with a method for producing the composition.
Sucralfate is a basic aluminum sucrose sulfate. As a peptic ulcer treating agent having a stromal protein protecting effect (gastric mucosa protecting effect), a gastric juice pepsin activity inhibiting effect, and an antacid effect, sucralfate is widely used for alleviation of gastric ulcer, duodenal ulcer, or gastric mucosal lesions in diseases, such as erosion, bleeding, redness or edema; for treatment of acute gastritis; and at the acute aggravated stage of chronic gastritis. Sucralfate shows a therapeutic effect by forming a bioadhesive paste upon reaction with gastric acid in the digestive tract to generate a local protective barrier, which protects the mucous membrane of the digestive tract from an excess of gastric acid, and promotes the in vivo repairing action on the mucosa.
Sucralfate has so far been supplied as a single-component pharmaceutical preparation, but in the clinical setting, it is generally used as a formulation combined with an antacid, etc. As an over-the-counter drug, sucralfate has been used as combined drugs. in the form of tablets, granules, fine granules, or suspension, in combination with various antacids, gastrointestinal drugs, or analgesic antispasmodics. To bind sucralfate to the site of ulceration effectively, it is important that a sucralfate preparation be rapidly disintegrated, and dispersed. For example, proposal has been made for a suspension comprising natural gums, deflocculants, and sucralfate (Japanese Unexamined Patent Publication No. 5-238938), or a sucralfate preparation obtained by adding a plasticizer to sucralfate, and granulating the mixture in molten condition (Japanese Unexamined Patent Publication No. 8-104637).
However, sucralfate is insoluble in water, and combined gastrointestinal drugs comprising sucralfate and various antacids lead to the instantaneous neutralization of gastric acid with the antacids to increase the pH in the stomach. Thus, the adhesion of sucralfate which should be generated upon reaction with gastric acid is delayed or inadequate, thereby failing to show a sufficient gastric mucosa protecting effect. Consequently, its antiulcer effect and its ulcer inhibiting/healing effect have sometimes been diminished.
The present invention aims to develop a coated antacid prescribed as a combined drug containing sucralfate. The combined drug, upon ingestion, prevents the deterioration of the adhesive substance forming characteristics of sucralfate, and can reliably exhibit its actions in the stomach.
That is, the combined drug suppresses the reaction of the antacid with gastric acid at the initial stage after it arrives at the stomach. By so doing, the drug enhances the solubility of sucralfate in the stomach, and permits sucralfate to show its antiulcer effect and its ulcer inhibiting/healing effect. Furthermore, the drug can make the antacid effect of the antacid persist sufficiently and for a long time after the sucralfate amply adheres to the mucosa. If the drug also contains other pharmacologically active ingredients, release of these active ingredients can also last for a long period of time. The present invention aims at developing a gastrointestinal drug which fulfills these requirements, and an antacid to be incorporated into this combined prescription.
The inventors conducted extensive studies to resolve this challenge. As a result, they found that a coated antacid obtained, for example, by spray drying a slurry of an antacid, together with a coating agent and a specific plasticizer, suspended in a suitable medium can control the onset of the reaction between gastric acid and the antacid. This coated antacid is an antacid having DDS function which can strictly control the onset of the reaction between gastric acid and the antacid, because the amount of mixing of the plasticizer to be spray dried, such as a polyethylene glycol, is adjusted to control the porosity and the pore size for the pore formation of the spray dried particles. Conventional sustained release antacids are slowly released. By contrast, the coated antacid of the present invention is characterized by delaying the onset of the reaction of the antacid.
The inventors found that a composition comprising the coated antacid and sucralfate, when orally administered as a gastrointestinal drug, not only shows the mucosa repairing action of sucralfate fully, but acts synergistically with the antacid effect and gastric mucosa protecting effect of the incorporated coated antacid, thus exhibiting an excellent antiulcer action and an excellent ulcer inhibiting and healing action. Based on this finding, they accomplished the present invention. When other pharmacologically active ingredient is incorporated in the composition of the invention, this active substance can be sustainedly released for a long time.